Bis-(3-benzyl-5-chloro-2-hydroxyphenyl)-methane antiseptic and preparation thereof



2,724,000 Patented Nov. 15, 1955 BIS-(3-BENZYL-5-CHLORO- 2 HYDRQXYPHENYD- ANTISEPTIC AND PREPARATION Douglas E. Cooper, Syracuse, and Lee C. Cheney, Fayetteville, Y., assignors to Bristol Laboratories Inc, Syracuse, N. Y., a corporation of New York No Drawing. Application December 1, 1951, Q

Serial.No.25 9,501

3 Claims. (Cl. 260-619) This invention relates to a new, hydroxylated, diphenylmethane having valuable uses as a bacterial agent and antiseptic. More specifically, this invention relates to 6,6- methylene-bis- 4-ch1oro alpha-phenyl-ortho-cresol) This application is a continuation-in-part of our prior pending application of Serial Number 244,729, filed August 31, 1951, and now abandoned.

The use of the class of substances often called methylene-bis-phenols as germicides, antiseptics and topical antibacterial agents has become generally recognized in the art. A principal problem has been to obtain a high degree of antibacterial efficacy withoutconcomitant, high toxicity toward the animal or human body. Consequently, much effort has been expended in the search for com-- pounds of increased eiiicacy and suitably low toxicity.

We have now discovered, according to the present invention, the new compound which has the following formula pH na @-o11 om-o Hip-Q 1 1 and is named 6,6'-methylene-bis-(4-chloro-alpha-phenylortho-cresol), according to the practice of Chemical Abstracts, but which may be designated properly also as bis- 3 -benzyl-5-chloro-2-hydroxyphenyl) methane.

We have also discovered that the product of the present invention is safe and highly effective as a bactericidal agent and antiseptic, particularly for topical use.

A typical example of the activity of the new hydroxylated diphenylmethane derivative in comparison with one of the best of the present members of the class of methylene-bis-phenols is obtained by tests against the standard pathogen Staphylococcus aureus, as measured in the serial dilution procedure. The results of this test are given in Table I. The compound used for comparison has usually been designated in commerce as G-ll or Hexachlorophene and was originally prepared by Gump (U. S. Patent 2,250,480).

TABLE I In vitro antibacterial activity Minimum Effective Con- Minimum concentration required to inhibit; completely the growth of the test organism, Staphylococcus aureus.

b Range of concentrations through which this compound exhibits partial to complete inhibition of the growth of the test organism, Staphylococcus aureus.

The greater potency of the compound I of thepresent invention is indicated by inspection of this data.

bis-phenols has been disclosed. However, the significance of the higher potency of this new hydroxylated diphenylmethane as an advance in the TABLE II Toxicity status As determined by these particular tests, the product of the present invention is about four times as potent and ment in terms of increased potency and decreased toxicity which has been achieved in the compound of the present invention.

6,6 methylene bis (4 chloro alpha phenylortho-cresol) is a white, crystalline, odorless and tasteless solid. It is readily soluble in alcohol, acetone and even hydrocarbon solvents. It may be emulsified using the common surface active agents or diethanolamine and its homologues. Its bacteriostatic activity is of sufiiciently high an order that eifective concentrations are readily attainable in virtually all types of product media; for example, an aqueous solution containing 0.062 milligram per milliliter completely inhibits the gram-negative organism E. 0011'.

A more comprehensive understanding of this invention is obtained by reference to the following examples, which are given by way of illustration and not of limitation.

EXAMPLE 1 A homogeneous solution is prepared by mixing a melt of 218 grams 2-benzyl-4-chloro-phenol with 70 ml. methanol and 45 ml. aqueous formaldehyde (37%). This is added at the rate of about 1 drop per second to 1100 ml. concentrated (93%) sulfuric acid stirred and maintained at 5 C. After addition is complete the brown slurry, still kept cold, is stirred an additional 16 hours.

To recover the product the mixture is poured into a large vessel containing 5 kilograms of ice, and the very bulky tan precipitate is washed copiously with Water to free it from acid. The filter cake, pressed as dry as practical, is digested for half an hour with a mixture of 1200 ml. 50% aqueous potassium hydroxide and 2800 ml. methanol. The suspension is then cooled and filtered. The filtrate is run in a steady stream over an hours duration into a stirred solution of 1000 grams potassium hydroxide in 14 liters of Water. The precipitate of insoluble monopotassium salt is separated by filtration, washed with water and dried. The yield is approximately grams.

This salt is soluble in boiling xylene and may be readily recrystallized from this medium, using approximately 15 ml. for each gram of salt. To obtain the free phenol the salt is triturated with twice its own weight of acetic acid and the slurry slowly diluted with volumes of water. The white crystalline product which, separated and dried, melts at approximately 100 C., may be further purified by recrystallization from a high boiling ligroin, as Skellysolve D. The pure compound thus obtained melts at 112-113" C.

Molecular weight-Calculated for C27H22O2Cl22 449. Found: (Rast camphor procedure) 473. Analysis-Calculated for Cz'zHzzOzClzz C, 72.3; H,

5.34. Found: C, 72.5; H, 5.34.

The compound may also be recrystallized from acetic acid. The crystals obtained from this solvent melt at 105-106 C. e

1 The-compound is only very slightly soluble in boiling 3% aqueous potassium hydroxide. Cooling such a solution deposits colorless needles of the monopotassium salt melting at 278-280 C.

' EXAMPLE 2 4 solidis washed with small volumes of acetic acid, cyclohexane, and finally petroleum ether (B. P. 28-37 C.). The white product weighs 18 to 22 grams and rnclts'at about 92 C.

The free phenol derivative is obtained by cautiously treating a solution of the solvent in 3 parts boiling cyclohexane with /2 part of anhydrous sodium carbonate added in small portions, refluxing the mixture, filtering while still hot, and allowing to cool slowly. The product separates as a white crystalline solid melting at 112-113 C. and weighing 15-18 grams.

We claim: 7

1. The compound 6,6' methylene-bis-(4-chloro-alphaphenyl-ortho-cresol).

2. The process of making 6,6'-methylene-bis-'(4-chloroalpha-phenyl-ortho-cresol) comprising reacting 2-benzyl 4-chlorophenol with a formaldehyde-yielding material in the presence of an acidic condensing agent, and purifying the product.

3. The process of making 6,6-methylene-bis'-(4-chloroalpha-phenyl-ortho-cresol) comprising reacting 2-benz'yl 4-chlorophenol with a formaldehyde-yielding' material in the presence of sulfuric acid, and purifying the product.

References Cited in the file of this patent UNITED STATES PATENTS 2,057,690 Moss Oct. 20, 1936 2,139,081 Honel- Dec. 6, 1938 2,249,460 DAlelio July'15, 1941 2,353,725

Gump July 18, 1944 

1. THE COMPOUND 6,6-METHYLENE-BIX(4-CHLORO-ALPHAPHENYL-ORTHO-CRESOL). 